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R. S. Golpanian et al.
itchy patients also excreted more chloroquine in
their urine than non-itchy patients, further suggesting less metabolism of the parent drug by
these patients (Ademowo etal. 2000).
Hydroxyethyl Starch
HES is a colloid traditionally used for volume
replacement and uid management. Up to 64%
of patients experience pruritus associated with
administration of this drug (Grochenig et al.
1998; Leunig etal. 1995; Murphy etal. 2001).
Most patients characterize the itching as generalized and severe, with a visual analogue scale
median score of 9 out of 10 (Ständer etal. 2014).
Lag period is usually delayed and is about
1–6weeks after initiation of HES infusion, and
the itching typically lasts 9–15weeks or longer
(Ebata 2016).
HES-induced pruritus is a form of neuropathic
itch, as deposition of this drug has been found in
Schwann cells of cutaneous nerves of itchy
patients. Drug deposits were also found in epithelia of sweat glands, endothelial cells of blood and
lymphatic vessels, dermal macrophages,
Langerhans cells, and basal keratinocytes
(Ständer etal. 2001). Drug deposition was shown
to be proportional to dosage, and more extensive
deposits were more likely to be seen in patients
who developed pruritus (Sirtl et al. 1999).
Furthermore, the disappearance of HES vacuoles
in cutaneous nerves paralleled the improvement
of pruritus (Metze etal. 1997). It remains unclear
how cells that contain HES provoke itching, but it
has been suggested that HES deposits may
mechanically irritate nerve endings (Roeser and
Tronnier 1990). Another possibility is that the
cells that contain drug deposits mediate pruritus
through the release of specic mediators.
Drugs Inducing Cholestasis
Cholestatic liver injury is one of the most common causes of drug-induced pruritus, as many
drugs are known to cause hepatotoxicity.
Cholestasis refers to stagnant bile that fails to
reach the duodenum (Degott 1997). The list of
drugs that may induce cholestatic liver injury is
quite extensive, and of note, antimicrobials are
the most common culprit (Lucena et al. 2009;
Bhamidimarri and Schiff 2013). Although every
single drug known to cause cholestatic liver
injury has not been shown to induce pruritus, one
can extrapolate that any drug which has the
potential to trigger this type of liver injury also
has the capability of inducing pruritus. Examples
of other drugs known to induce pruritus secondary to cholestasis include ACE inhibitors, calcium channel blockers, tricyclic antidepressants,
and oral contraceptives.
Patients with drug-induced cholestasis may
present with a variety of symptoms, including
pruritus with or without jaundice (Bhamidimarri
and Schiff 2013). Itching has been shown to be
most intense in the palms and soles; however it
may also be generalized (Pusl and Beuers 2006;
Bergasa etal. 2000). Lag time from treatment initiation to onset of pruritus can range from a few
weeks to many months (Orme and Da Costa
1997; Mikhail 2004; Amaro et al. 1999;
Quattropani et al. 2001; Hunt and Washington
1994). Furthermore, drugs known to induce cho-
lestasis may cause itch that does not remit until
months after drug cessation (Kowdley etal. 1992;
Larrey etal. 1988).
The exact mechanism by which cholestasis
results in itch is still unclear; however, the
pathophysiology is likely multifactorial. Bile
salt accumulation is a postulated mechanism of
pruritus, and there is recent evidence that
MrgprX4 is a bile acid receptor for cholestatic
itch (Quist etal. 1991; Yu etal. 2019). A component of neurogenic itch in which pruritus originates centrally but without evidence of neural
pathology is likely, as it has been proposed that
cholestatic injury results in the accumulation of
pruritogens such as endogenous opioids (Swain
etal. 1992). It has been hypothesized that the
expression of lysophosphatidic acid (LPA) by
autotaxin activates unmyelinated nerve endings
that transmit itch in cholestasis (Elferink etal.
2011).
Anticancer Therapies
Targeted anticancer therapies are novel drugs that
have led to a signicant increase in survival rates
among various cancer patients. Unfortunately,
they are also associated with many unwanted side
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219
effects, including pruritus without rash. When
379 cancer survivors were asked about their perceptions of treatment-related dermatologic toxicities, the third most common dermatologic side
effect reported was pruritus (accounting for 36%
of patients), and 44% of this patient cohort experienced a negative impact on their quality of life
as a result of this side effect (Gandhi etal. 2010).
A systematic review and meta-analysis ascertaining the risk of pruritus among patients treated
with targeted anticancer therapies found that
these patients had a signicant risk of developing
pruritus, with an overall incidence of 17%
(Ensslin etal. 2013).
The mechanism of action of pruritus in targeted anticancer therapies depends on the drug
class.
Epidermal growth factor receptor (EGFR)
inhibitors such as panitumumab are proposed to
produce itch through direct skin barrier disruption. Binding of these drugs to the EGFR (epidermal growth factor inhibitor) in the basal layer of
proliferating keratinocytes can result in abnormal
proliferation and migration of these cells.
Furthermore, these drugs may cause sebaceous
and sweat gland dysfunction as well that can contribute to dry skin and itch (Fischer etal. 2013).
PD-1 inhibitors such as pembrolizumab block
the interaction of the PD-1 receptor with its
ligand (PD-L), an interaction that normally inhibits T cell proliferation and reduces cytokine load
(Belum etal. 2016).
Interestingly, a study by Huber etal. showed
that blockade of PD-L2, a ligand for the PD-1
receptor, caused an enhanced Th2 response
(Huber etal. 2010). As Th2 cells are known to
produce IL-31, a pruritic cytokine, it is possible
that PD-1 inhibitors induce pruritus through their
induction of the Th2 immune response
(Kabashima 2013; Raap et al. 2012; Gutzmer
etal. 2009).
Tyrosine kinase inhibitors such as imatinib
mesylate have been implicated in drug-induced
itch, with frequencies of all-grade pruritus of up
to 10% (Yosipovitch 2018). This drug selectively
targets protooncogenes such as Abl, c-Kit, and
the platelet-derived growth factor (PDGF) receptor. Although human mast cells express the c-kit
receptor which is susceptible to inhibition by
imatinib, a paradoxical increase in the number of
dermal mast cells has been identied in patients
on a high-dose imatinib regimen (Ugurel etal.
2003; Ma et al. 2002). Furthermore, levels of
IL-31 and IL-33 have been identied in the serum
of patients undergoing imatinib therapy
(Musolino et al. 2015). These ndings taken
together have led to the postulation that keratinocyte injury secondary to imatinib usage may
cause the release of IL-33, which interacts with
mast cells to aid in the induction of chemoattractants such as IL-31, a known itchy cytokine
(Musolino etal. 2015).
Finally, IL-2 is an anticancer therapy that has
been shown to cause pruritus in up to 65% of
patients. This is not surprising as IL-2 is among
the many known pruritogenic cytokines and has
been shown to play a role in eliciting itch in
inammatory skin diseases such as atopic dermatitis (Yosipovitch and Papoiu 2008; Chi et al.
2001; Redman etal. 1990).
Other Drugs
Angiotensin-converting enzyme (ACE) inhibitors are widely used drugs for the treatment of
hypertension and, in a large multicenter study,
were shown to cause pruritus without rash in up
to 61% of patients (Huang etal. 2019). Additional
reports of ACE inhibitors causing pruritus have
been published (Steckelings etal. 2001; ThestrupPedersen 1987; Gibbs etal. 1999). ACE inhibitors degrade bradykinin, an inammatory
mediator that has been shown to activate itch
bers.
Serotonin-reuptake inhibitors have been
shown to produce pruritus without rash in up to
54% of patients (Huang etal. 2019). Serotonin
has also been shown to cause itch when intradermally injected (Weisshaar et al. 1997). It has
been shown that serotonin can act as a pruritogen
by acting on the 5-HT2 receptor, and that central
5-hydroxytryptophan (5-HT) signaling facilitates
itch transmission (Yosipovitch etal. 2018; Zhao
etal. 2014). Interestingly, these drugs have also
been used as successful treatment for pruritus,
highlighting the complexity regarding itch transmission (Leslie etal. 2015).
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R. S. Golpanian et al.
Statins are drugs that have revolutionized lipid
management and work through their modulation
of lipid metabolism and inhibition of cholesterol
biosynthesis (Stancu and Sima 2001). Statins
may cause drug-induced pruritus directly secondary to xerosis cutis; however this side effect is
quite rare, as these drugs also have an antiinammatory component that may reduce itch
(Huang etal. 2019; Garibyan etal. 2013). Note
that statin-induced pruritus is likely to be multifactorial, as these drugs have been reported to
induce pruritus indirectly through their cholestatic effects as well (Kashyap etal. 2002; Sharma
etal. 2006; Russo etal. 2009, 2014).
5 Diagnosis
Drug-induced pruritus may be difcult to diagnose due to the abundance of triggers that may
induce itching, such as the primary disease for
which the medication has been prescribed (i.e.,
cancer), the medical background of the patient
(i.e., atopic predisposition, liver disease, and
chronic renal disease), and other factors (i.e.,
allergies). Proof of diagnosis is challenging and
may be supported through clinical improvement
of symptoms upon drug cessation. However, pruritus may continue in some cases even though the
offending drug has been discontinued, as elaborated above.
When a patient complains of pruritus and
drug-induced itch is highly suspected, a thorough history and physical exam should be performed. All components of the patient history
are important, including past medical history,
family history, and allergies, including personal
and family atopic background. Also, a list of all
drugs the patient has been prescribed, including
dietary supplements and vitamins, should be
recorded. Features of the pruritus should be
assessed, including onset timing following drug
initiation, intensity, location, quality, and time of
day during which the itching occurs. Alleviating
or aggravating factors should be elucidated as
well, such as exposure to hot water, sweating,
temperature changes, and response to various
treatments.
Physical exam should include inspection of
the entire skin, hair, and nails. Lymph node
enlargement and organomegaly should also be
assessed. It is crucial to differentiate between
primary and secondary lesions of the skin, as
drug- induced pruritus does not include primary
skin lesions. However, intense rubbing and
scratching of the skin induces various secondary
skin lesions, such as excoriations (linear or
punctate) and thickened and leathery skin with
exacerbated markings (lichenication). A diagnosis of drug- induced pruritus is also to be differentiated from the various pruritic rashes that
may also be induced by drugs, such as psoriasiform rashes, induction of eczema, drug-induced
bullous pemphigoid, etc. Diagnostic testing
should include complete blood count and full
chemistries, including renal and liver function
tests.
6 Treatment
Once an offending drug is suspected, discontinuing the drug should be a consideration. However,
a risk-benet analysis for each case needs to be
considered where the benet of medical treatment with the drug outweighs the decrease in
patient quality of life arising from the pruritus.
Most causes of drug-induced pruritus typically
resolve after cessation of the culprit drug
(Nammour et al. 2003; Aggarwal et al. 2011;
O’Beirne and Cairns 2001). In cases where the
offending drug is not discontinued, treatment
should instead focus on symptomatic relief. Mild
pruritus that is localized can be treated topically
with local anesthetics such as pramoxine, cooling
agents such as menthol and calamine, ion channel
inhibitors such as strontium, or combined application of ketamine-amitriptyline-lidocaine.
Application of cool temperature may also be
helpful in attenuating itch. For more severe, generalized itch, systemic therapy such as gabapentin or pregabalin, antidepressants such as
mirtazapine and paroxetine, butorphanol, and
phototherapy should be considered (Yosipovitch
et al. 2018; Ensslin et al. 2013; Santini et al.
2012). Aprepitant may be helpful specically for
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221
the management of severe pruritus related to anticancer treatments (Santini etal. 2012).
If drug cessation does not result in relief of
symptoms, treatment options may depend on the
culprit drug. For example, opioid-induced itch has
successfully been treated with naloxone, nalbuphine, butorphanol, and ondansetron (Gan et al.
1997; Korhonen etal. 2003; Alhashemi etal. 1997).
First-line treatment of chloroquine- induced itch is
antihistamines; however prednisolone, niacin, and
naltrexone have been used as well (Bussaratid etal.
2000; Adebayo et al. 1997; Ajayi et al. 2004).
Chronic itch induced by HES can be treated with
topical capsaicin, UV therapy, or naltrexone
(Szeimies et al. 1994; Metze et al. 1999). Drugs
that induce itch indirectly through cholestatic liver
injury should be treated with ursodeoxycholic acid,
rifampin, or cholestyramine (Ebata 2016).
7 Conclusion
Drug-induced pruritus accounts for a great proportion of adverse drug reactions. Although common,
this adverse reaction can be quite elusive, as pruritus manifests without coexisting skin lesions, and
many drugs of different classes have the potential
to cause this medical problem. Nevertheless, clinicians must be able to identify this adverse reaction
and importantly, to distinguish it from pruritus
secondary to a skin eruption. While several putative mechanisms of drug-induced pruritus have
been elucidated, in most cases, the role of the drug
in the itch pathway remains unclear. Further studies clarifying such mechanisms may help guide
future treatment.
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Drug-Induced Nail Changes
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Chia-ChunAng andEckartHaneke
1 Introduction
Adverse drug reactions can affect multiple organs
in the body. The effects of drug reactions on skin,
hair, and nails are most accessible to clinical
examination and may thus provide the earliest
clinical clues. Nail changes in particular can persist for months, giving a clue to a drug-induced
reaction from the recent past. Some drug-induced
nail toxicity can lead to signicant morbidity. In
this short review, we aim to provide a framework
to assess and manage drug reactions of the nail
unit. The strength of evidence for many druginduced nail changes is limited to case reports
and in some cases the causality is difcult to
determine, with the possibility of the nail changes
being due to the underlying medical condition.
While we strive to highlight known associations
for drug-induced nail changes, our review is not
exhaustive, and readers are encouraged to review
the literature as part of their diagnostic consideration when they encounter patients with suspected drug-induced nail changes.
C.-C. Ang (*)
Department of Dermatology, Singapore General
Hospital, Singapore, Singapore
e-mail: Ang.chia.chun@singhealth.com.sg
E. Haneke (*)
Department of Dermatology, Inselspital—University
of Bern, Bern, Switzerland
2 Human Nail Unit Anatomy
withPathophysiological
Correlation
A drug can affect the nail unit through its usual
mechanism of action (e.g., cytotoxicity of chemotherapeutic agents on the dividing cells of the nail
matrix), from direct involvement of the matrix,
nail bed, and/or periungual skin in a great number
of inammatory cutaneous drug reactions, or from
deposition of the drug or its metabolites in the nail
unit, although in some cases the exact causative
mechanism is unknown. The clinical picture
depends on which part of the nail unit is affected.
Usually more than one nail is affected by a systemically administered drug, and the nail changes
appear earlier in the faster growing ngernails
compared to the toenails (Piraccini etal. 2004).
The nail unit consists of the nail plate, which is
surrounded proximally by the proximal nail fold
and cuticle, laterally by the lateral nail folds, and
distally by the hyponychium. Periungual granulation tissue (incorrectly referred to as drug-induced
periungual pyogenic granuloma by some authors)
and acute paronychia (Fig.1a, b) occur along the
proximal and lateral nail folds from a combination of drug-induced nail plate brittleness (leading
to ingrowing nail), fragility of the epidermis due
to decreased epidermal proliferation, and druginduced predisposition to granulation tissue formation. Synthetic retinoids, reverse transcriptase
inhibitors, and, in particular, epidermal growth
© Springer Nature Switzerland AG 2022
H. Y. Lee, D. Creamer (eds.), Drug Eruptions, Updates in Clinical Dermatology,
https://doi.org/10.1007/978-3-031-09388-3_19
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